The solid phase synthesis of non-peptidic small organic molecules is a rapidly evolving area of research with applications in the preparation of combinatorial libraries. While the solid phase synthesis of peptides is an established, the solid phase synthesis of non-peptidic small organic molecules is still evolving (Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527-4554). In particular, methods for the solid phase synthesis of heterocyclic ring systems of importance to drug discovery is an active area of research.
Indoles are an important class of molecules with physiological significance and pharmaceutical utility. In synthetic and natural product chemistry, the indole ring system has broad pharmacological activity (Sundberg, R. J. in Comprehensive Medicinal Chemistry, Vol. 4, pp. 370-376; Pergamon Press: Oxford, 1984). An example of the physiological significance of the indole ring system is serotonin, which is of overwhelming importance for normal psychological function. Two important pharmaceutical areas are anti-inflammatory drugs such as indomethacin and drugs acting on the central nervous system. Indoles have also found use in other therapeutic areas.
Combinatorial chemistry is becoming an important tool for drug discovery and lead optimization (Borman, S. Chemical and Engineering News 1997, 75 (8), 43-62). A combinatorial synthesis requires that at least two components of the product molecules be independently variable, so that all of the combinations of these components can be prepared. A synthesis with three independently variable components is preferable since greater diversity in structure can be produced in the resultant library. Thus, to prepare a combinatorial library of indoles with a high degree of potential diversity and wide utility for drug discovery using solid phase techniques, it is important to identify an indole synthesis in which three components can be independently varied. The solution phase synthesis of indoles reported by Arcadi and Cacchi (Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1992, 33, 3915-3918) incorporates two components in an independent fashion through palladium-catalyzed processes. The indoles prepared by this route can then be alkylated on nitrogen to incorporate a third component. By adapting the solution phase synthesis to a solid-supported synthesis, it is possible to prepare combinatorial libraries of indoles at room temperature under neutral or mildly basic conditions and thus there are few limitations to the solid support and linker used.
A solid phase synthesis of indoles requiring elevated temperatures and acidic conditions has been reported (Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996, 37, 4869-4872). The solid-phase Fisher indole synthesis requires elevated temperatures and acidic conditions which limit the types of linkers and solid supports that can be used for the synthesis. Fagnola et al., Tetrahedron Letters 1997, 38, (13), 2307-2310, disclose a solid phase synthesis of 2-substituted indoles using the palladium-catalysed coupling of alkynes with N-acetyl iodoaniline derivatives. Only one variable group is introduced in the synthesis so it is not ideal for the preparation of combinatorial libraries.
Multiple compounds can be prepared simultaneously by the solid phase process. The simultaneous solid phase synthesis of a library of 2,3-disubstituted indoles of the present invention is not known. The preparation of libraries of compounds of the present invention is useful because it provides rapid structural variation and structure-activity information.
The libraries of substituted indoles synthesized according to the present invention are useful for drug discovery. For example, screening one of the indole libraries in an estrogen receptor assay identified compounds with estrogen agonist activity. Estrogen agonists are useful as post-menopausal therapeutics for the prevention and treatment of osteoporosis, atherosclerosis, and Alzheimer's disease.